Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family

Yonghong Li, Petra Nowotny, Peter Holmans, Scott Smemo, John S.K. Kauwe, Anthony L. Hinrichs, Kristina Tacey, Lisa Doil, Ryan Van Luchene, Veronica Garcia, Charles Rowland, Steve Schrodi, Diane Leong, Goran Gogic, Joanne Chan, Anibal Cravchik, David Ross, Kit Lau, Shirley Kwok, Sheng Yung ChangJoe Catanese, John Sninsky, Thomas J. White, John Hardy, John Powell, Simon Lovestone, John C. Morris, Leon Thal, Michael Owen, Julie Williams, Alison Goate, Andrew Grupe

Research output: Contribution to journalArticlepeer-review

122 Scopus citations

Abstract

Although several genes have been implicated in the development of the early-onset autosomal dominant form of AlzheimeKs disease (AD), the genetics of late-onset AD (LOAD) is complex. Loci on several chromosomes have been linked to the disease, but so far only the apolipoprotein E gene has been consistently shown to be a risk factor. We have performed a large-scale single-nucleotide polymorphism (SNP)-based association study, across the region of linkage on chromosome 12, in multiple case-control series totaling 1,089 LOAD patients and 1,196 control subjects and report association with SNPs in the glyceraldehyde-3-phosphate dehydrogenase (G-APD) gene. Subsequent analysis of G-APD paralogs on other chromosomes demonstrated association with two other paralogs. A significant association between LOAD and a compound genotype of the three GAPD genes was observed in all three sample sets. Individually, these SNPs make differential contributions to disease risk in each of the case-control series, suggesting that variants in functionally similar genes may account for series-to-series heterogeneity of disease risk. Our observations raise the possibility that GAPD genes are AD risk factors, a hypothesis that is consistent with the role of GAPD in neuronal apoptosis.

Original languageEnglish
Pages (from-to)15688-15693
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number44
DOIs
StatePublished - Nov 2 2004

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